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Sildenafil was administered intravaginally during the proliferative phase of the menstrual cycle for 3 or 6 days. NK cells activity was also investigated in in vitro cultures of mononuclear cells (MNC) of the patients and the control group. Sildenafil added at the 10 ? g/mL concentration to the culture of MNC of healthy women reduced NK cell activity [50].

Determination of serum TNF- ? level revealed a tendency to increase after sildenafil therapy [51].

These results were in contrast with the findings of El-Far et al. In the latter study, the percentages of CD3 + CD56 + CD161 + NKT cells and TNF- ? positive T cells were greatly reduced after sildenafil intravaginal administration (25 mg/4 times a day for 24 days). The differences could be explained by different dosing of the drug.

Preeclampsia is a disorder of pregnancy characterized by high blood pressure and level of protein in urine, due to endothelial dysfunction and is a primary cause of maternal morbidity.

It affects 2–8% of pregnancies worldwide, and, if not treated, leads to eclampsia. Complications include aspiration pneumonia, cerebral hemorrhage, kidney failure, and cardiac arrest [53]. The vascular endothelial grow factors (VEGFs) family of proteins and their receptors are thought to be key contributors to this disease.

It is believed that high level of VEGF and placental growth factor (PLGF) are involved in vascular remodeling of cytotrophoblast.

The VEGF-receptor-1 is denoted as soluble fms-like tyrosine kinase-1 (sFlt-1) as it belongs to fms related tyrosine kinase family. Placenta of pregnant women with preeclampsia produces high levels of sFlt-1.

sFlt-1 binds to free VEGF and PLGF, inactivates them, and makes them unavailable for proper signaling [54].

Advanced glycation end-products (AGEs) represent the molecular complexes generated as a result of nonenzymatic reactions of carbohydrates and oxidized lipid with proteins.

These reactions lead to the irreversible cross-linking of proteins and, as a consequence, loss of protein structure and function. Previous studies demonstrated that serum AGEs in preeclamptic women were significantly higher than in healthy women.

Accumulation of AGEs may induce oxidative injury and vascular perturbation in placental bed, leading to preeclampsia [55]. showed that AGEs contribute to elevation of sFlt-1.

The study was conducted on JEG-3 cell line established from choriocarcinoma that was shown to retain trophoblastic cell-like characteristics. They observed that AGEs-BSA increased sFlt-1 mRNA expression and protein release as well as increasing the production of ROS and NF- ? B in JEG-3. Sildenafil citrate suppressed sFlt-1 mRNA expression and protein release in cells treated with AGEs-Bovine Serum Albumin in a dose-dependent manner (concentration range 5–100 ? mol/mL) [56]. Unexpected results of healing of one patient from B-cell chronic lymphocytic leukemia (B-CLL) treated only with sildenafil were reported by Sarfati et al.

During a 3.

5-year

In addition, sildenafil induced apoptosis of the B-CLL cells in caspase 3-dependent way in vitro.

It has been shown that IL-4 abrogated the effect of sildenafil. Interestingly, there was no killing effect of sildenafil on normal B-cells.

[58] reported similar findings in 5 patients suffering from Waldenstrom’s macroglobulinemia (WM) and erectile dysfunction.

WM tumor cells were also culture-sorted with sildenafil at pharmacologically relevant levels and apoptosis was demonstrated in tumor cells from all 5 patients. Possibly, the modulating effect of sildenafil on lymphocyte subpopulations and humoral immune responses is also mediated by the synthesis and release of cytokines [21, 22, 59]. Sildenafil improves the condition of patients with Reynaud’s phenomenon and helps wound healing in scleroderma by inhibiting the TGF- ? –Rho kinase pathway.

TGF- ? acts as an antiproliferative factor in normal epithelial cells and at the early stages of oncogenesis [60, 61]. Some cells which secrete TGF- ? also have receptors for this cytokine, a phenomenon known as autocrine signaling.

Cancer cells increase production of TGF- ? , which also affects the surrounding cells.

The Rho GTPases are involved in numerous signal female viagra order online transduction pathways and act as regulators of the actin cytoskeleton, cell motility, and transcription. They are associated with progression to malignancy in several types of cancer.

The Rho GTPases are molecular switches which remain inactive when GDP bound and active when GTP bound, and they expand their signals through interaction with numerous downstream signaling effectors [62–64]. In this way it is possible that sildenafil affects oncogenesis.

[65] suggested that sildenafil inhibits RhoA/Rho kinase-dependent functions in the pulmonary artery through enhanced RhoA phosphorylation and cytosolic sequestration by GDP.

The inhibition of intracellular events downstream of RhoA thus participates in the beneficial effect of sildenafil in pulmonary hypertension. [66] described a patient with multiple sclerosis who developed severe PAH after treatment with IFN- ? -1a.

Sildenafil reversed the detrimental effect of IFN- ? on the cardiovascular system.

Reduced NO production is correlated with poor wound healing in diabetic patients. Sildenafil improved the production of NO in diabetic subjects.

Chronic administration of sildenafil in diabetic patients was associated with an increase in nitrite/nitrate levels and improved markers of vascular inflammation with a decrease of endothelin-1, IL-6 level, lower expression of integrins, including intracellular adhesion molecules (ICAM), and vascular adhesion molecules (VCAM).

Furthermore, the effect of sildenafil therapy was sustained after one month from withdrawal of the drug [67, 68].

A growing body of evidence shows that sildenafil exerts immunomodulatory effects.

Its positive action was demonstrated in treating severe autoimmune diseases and cancer. In addition, anti-inflammatory and antiaggregation effects of sildenafil have also been reported.

In tumor-bearing mice, the inhibition of PDE5 activity with sildenafil prolonged the survival of the animals through augmentation of antitumor immunity.

Daily sildenafil treatment from EAE symptom onset prevented further clinical deterioration and improved neurogenesis.

Sildenafil decreased the levels of proinflammatory cytokines, including TNF- ? , IL-1, and reduced NK cells activity, and enhanced the action of regulatory T cells. Sildenafil markedly inhibited iROS production induced by LPS.

Type 5 phosphodiesterase (PDE5) inhibitor increased endothelial cell cGMP and promoted angiogenesis by increasing the expression of VEGF. De novo blood vessel formation is essential for embryonic vascular development and for postnatal vascular homeostasis and wound healing.

Thus, the available data suggest that sildenafil could find use in the treatment of autoimmune, neurodegenerative, and cardiovascular diseases, as well as recurrent abortions.

However, the potential immunomodulatory effects of sildenafil in humans remain to be confirmed. B-CLL: B-cell chronic lymphocytic leukemia cGMP: Cyclic guanosine monophosphate ED: Erectile dysfunction GMP: Guanosine monophosphate IL: Interleukin NKT: Natural killer T-cells NO: Nitric oxide NOS: Nitric oxide synthase PDE-Is: Phosphodiesterase inhibitors PDEs: Phophodiesterases PKG: Protein kinase G ROS-Nrf2: Reactive oxygen species-nuclear erythroid 2-related factor 2 SC: Sildenafil citrate sGC: Soluble guanylate cyclase TGF- ? : Transforming growth factor- ? TNF- ? : Tumor necrosis factor- ? Treg: Lymphocyte T regulatory cells.

The authors declare that they have no competing interests. This work was supported by a grant from National Science Centre, Poland (NSC), no.

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